1. Field of the Invention
The present invention relates to novel pyrazole compounds which have potent inhibitory activity selectively against ROS kinase, and pharmaceutically acceptable salts thereof. Also, the present invention relates to anticancer agents comprising the novel pyrazole compounds or pharmaceutically acceptable salts thereof as active ingredients, useful in the prophylaxis and treatment of cancer associated with ROS kinase. Further, the present invention is concerned with a method for the preparation of the novel pyrazole compounds or pharmaceutically acceptable salts thereof.
2. Description of the Related Art
Signal transduction is an essential biological process for normal cell growth and function. In vivo, signals can be transmitted in various manners. A typical example of signal transduction is the transmission of signals into cells by a group of trans-membrane proteins with intrinsic tyrosine kinase activity, named receptor tyrosine kinases (RTKs) [Hubbard, S. R.; Miller, W. T. Curr. Opin. Cell Biol., 2007, 19, 117]. Mutations at RTK encoding genes are associated with the incidence of several types of cancers [Sequist, L. V.; Lynch, T. J. Annu. Rev. Med., 2008, 59, 429]. Among RTKs, ROS kinase, when mutated, is causative of various kinds of CNS malignancies including brain cancer, glioblastoma multiforme and glioblastoma [Birchmeier, C.; Sharma, S.; Wigler, M. Proc. Natl. Acad. Sci. U.S.A., 1987, 84, 9270].
The ectopic expression of ROS1 receptor protein has been reported mainly in meningiomas and astrocytomas (25% of low-grade astrocytomas and 30% of malignant glioma tumors) [Charest, A.; Kheifets, V.; Park, J.; Lane, K.; Mcmahon, K.; Nutt, C. L.; Housman, D. Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 916]. Glioblastoma multiforme is the most advanced astrocytic neoplasm, and is one of the most aggressive human cancers with a median survival of less than one year. These tumors are highly resistant to radiation and chemotherapy. Glioblastoma multiforme is also associated with ROS kinase activity [Holland, E. C. Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 6242].
No ROS kinase inhibitors have been developed thus far. Only several compounds are known to have weak inhibitory activity against ROS enzymes. For example, IC50 values are reported to be 0.9 nM for the non-selective kinase inhibitor Staurosporine, 5,200 nM for PP2, 13,600 nM for AG1478, 48,000 nM for PDGFR I-III and 365,000 nM for D-64406 [see the website of Reaction Biology Corporation, www.reactionbiology.com].
In U.S., there are about 20,000 new astrocytomas diagnosed every year, and the number of people suffering from astrocytomas in the world has been in drastic increase in recent years. Brain cancer and spinal cord cancer account for 20% of the cases of childhood cancer. Further, 20% of childhood brain cancer and spinal cord cancer cases are found in children of the age of 15 years or less, with the most intensive incidence in children between the ages of five and ten years. Particularly, neuroblastoma, for the most part, occurs at the age of five or less, with a very high mortality [Brard, L.; Singh, R. K.; Kim, K. K.; Lange, T. S.; Sholler, G. L. S., Drug Design, Development and Therapy, 2008, 2, 61].
Leading to the present invention, intensive and thorough research into ROS kinase inhibitors, conducted by the present inventors, resulted in the finding that novel pyrazole compounds are of potent inhibitory activity against ROS kinase with a high selectivity therefor.